Mitochondrial Dysfunction and Increased Reactive Oxygen Species Impair Insulin Secretion in Sphingomyelin Synthase 1-null Mice

Yano, Masato; Watanabe, Ken; Yamamoto, Tadashi; Ikeda, Kazutaka; Senokuchi, Takafumi; Lu, Mei-Hong; Kadomatsu, Tsuyoshi; Tsukano, Hiroto; Ikawa, Masahito; Okabe, Masaru; Yamaoka, Shohei; Okazaki, Toshiro; Umehara, Hisanori; Gotoh, Tomomi; Song, Wen Jie; Node, Koichi; Taguchi, Ryo; Yamagata, Kazuya; Oike, Yuichi

doi:10.1074/jbc.m110.179176

Cited by 136 publications

(120 citation statements)

References 49 publications

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“…Similarly, our data suggest a link between serum sphingomyelin and insulin secretion. The mechanism explaining this relationship is not known, but sphingomyelin synthase 1 knockout mice have decreased plasma and islet sphingomyelin levels, glucose intolerance, and deficiencies in insulin secretion (25,40). Therefore, some sphingomyelin species are important players in maintaining glucose homeostasis.…”

Section: Discussionmentioning

confidence: 99%

Serum sphingolipids: relationships to insulin sensitivity and changes with exercise in humans

Bergman

Brozinick

Strauss

et al. 2015

American Journal of Physiology-Endocrinology and Metabolism

130

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Ceramides and sphingolipids are a family of lipid molecules that circulate in serum and accumulate in skeletal muscle, promoting insulin resistance. Plasma ceramide and dihydroceramide are related to insulin resistance, yet less is known regarding other ceramide and sphingolipid species. Despite its association with insulin sensitivity, chronic endurance exercise training does not change plasma ceramide and sphingolipid content, with little known regarding a single bout of exercise. We measured basal relationships and the effect of acute exercise (1.5 h at 50% V O2 max) and recovery on serum ceramide and sphingolipid content in sedentary obese individuals, endurancetrained athletes, and individuals with type 2 diabetes (T2D). Basal serum C18:0, C20:0, and C24:1 ceramide and C18:0 and total dihydroceramide were significantly higher in T2D and, along with C16:0 ceramide and C18:0 sphingomyelin, correlated positively with insulin resistance. Acute exercise significantly increased serum ceramide, glucosylceramide, and GM3 gangliosides, which largely decreased to basal values in recovery. Sphingosine 1-phosphate and sphingomyelin did not change during exercise but decreased below basal values in recovery. Serum C16:0 and C18:0 ceramide and C18:0 sphingomyelin, but not the total concentrations of either of them, were positively correlated with markers of muscle NF-B activation, suggesting that specific species activate intracellular inflammation. Interestingly, a subset of sphingomyelin species, notably C14:0, C22:3, and C24:4 species, was positively associated with insulin secretion and glucose tolerance. Together, these data show that unique ceramide and sphingolipid species associate with either protective or deleterious features for diabetes and could provide novel therapeutic targets for the future. insulin sensitivity; athlete's paradox; lipid composition; plasma biomarkers THE GLOBAL BURDEN OF DIABETES continues to rise, fueled by the even greater epidemic of prediabetes (9). Nevertheless, not all of those with prediabetes will develop diabetes (27), highlighting the need to identify nonglycemic markers of disease progression that may also prove useful as new targets for the treatment of diabetes itself. Advances in lipidomics have provided new tools to investigate processes that govern the development of diabetes and its complications beyond that of glucose itself. Serum ceramides, a family of sphingolipids involved in diverse and relevant metabolic processes, have received considerable attention in relation to diabetes, making them prime candidates for further examination. Unlike other biomarkers, discrete serum ceramide profiles are rendered across the spectrum of diabetogenesis, creating speculation that ceramides not only mark but contribute to the disease process (8, 17).Much of this speculation is derived from data generated from in vitro and animal experimentation. Human data to date are limited largely to associations between serum ceramide concentration and risk for both diabetes (15) and related comp...

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Section: Discussionmentioning

confidence: 99%

Serum sphingolipids: relationships to insulin sensitivity and changes with exercise in humans

Bergman

Brozinick

Strauss

et al. 2015

American Journal of Physiology-Endocrinology and Metabolism

130

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“…Generation of SM-reconstituted Cells-The generation and analysis of SMS1 knock-out mice have been described previously (15). We generated double knock-out mice lacking both SMS1 and SMS2 and isolated mouse embryonic fibroblasts (MEF) from the mouse embryo.…”

Section: Methodsmentioning

confidence: 99%

“…All experiments were performed using N8 generation, which was obtained by eight rounds of backcrossing to C57BL/6 (B6.129-sgms2 tmlKenw ). The generation of SMS1 knock-out mice has described previously (15). Leptin-deficient ob/ob mice were obtained from Japan SLC Inc. (Hamamatsu, Japan).…”

Section: Methodsmentioning

confidence: 99%

Dynamic Modification of Sphingomyelin in Lipid Microdomains Controls Development of Obesity, Fatty Liver, and Type 2 Diabetes

Mitsutake

Zama

Yokota

et al. 2011

Journal of Biological Chemistry

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169

170

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Lipid microdomains or caveolae, small invaginations of plasma membrane, have emerged as important elements for lipid uptake and glucose homeostasis. Sphingomyelin (SM) is one of the major phospholipids of the lipid microdomains. In this study, we investigated the physiological function of sphingomyelin synthase 2 (SMS2) using SMS2 knock-out mice, and we found that SMS2 deficiency prevents high fat diet-induced obesity and insulin resistance. Interestingly, in the liver of SMS2 knock-out mice, large and mature lipid droplets were scarcely observed. Treatment with siRNA for SMS2 also decreased the large lipid droplets in HepG2 cells. Additionally, the siRNA of SMS2 decreased the accumulation of triglyceride in liver of leptin-deficient (ob/ob) mice, strongly suggesting that SMS2 is involved in lipid droplet formation. Furthermore, we found that SMS2 exists in lipid microdomains and partially associates with the fatty acid transporter CD36/FAT and with caveolin 1, a scaffolding protein of caveolae. Because CD36/FAT and caveolin 1 exist in lipid microdomains and are coordinately involved in lipid droplet formation, SMS2 is implicated in the modulation of the SM in lipid microdomains, resulting in the regulation of CD36/FAT and caveolae. Here, we established new cell lines, in which we can completely distinguish SMS2 activity from SMS1 activity, and we demonstrated that SMS2 could convert ceramide produced in the outer leaflet of the plasma membrane into SM. Our findings demonstrate the novel and dynamic regulation of lipid microdomains via conformational changes in lipids on the plasma membrane by SMS2, which is responsible for obesity and type 2 diabetes.

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“…To determine whether these changes are attributable to increased oxidative stress in those tissues, we treated mice with the potent antioxidant NAC by including it in their drinking water (25). Immunoblot analysis using anti-4-HNE antibody of skin tissues harvested 7 weeks after initiating chemical application indicated that levels of reactive oxygen species (ROS) in NAC-treated K14-Angptl2 Tg mice were significantly lower than those seen in Tg mice not treated with NAC ( Fig.…”

Section: Increased Oxidative Stress Parallels Angptl2 Expression In Mmentioning

confidence: 99%

Angiopoietin-like Protein 2 Accelerates Carcinogenesis by Activating Chronic Inflammation and Oxidative Stress

Aoi

Endo

Kadomatsu

et al. 2014

Molecular Cancer Research

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Chronic inflammation has received much attention as a risk factor for carcinogenesis. We recently reported that Angiopoietin-like protein 2 (Angptl2) facilitates inflammatory carcinogenesis and metastasis in a chemically induced squamous cell carcinoma (SCC) of the skin mouse model. In particular, we demonstrated that Angptl2-induced inflammation enhanced susceptibility of skin tissues to "preneoplastic change" and "malignant conversion" in SCC development; however, mechanisms underlying this activity remain unclear. Using this model, we now report that transgenic mice overexpressing Angptl2 in skin epithelial cells (K14-Angptl2 Tg mice) show enhanced oxidative stress in these tissues. Conversely, in the context of this model, Angptl2 knockout (KO) mice show significantly decreased oxidative stress in skin tissue as well as a lower incidence of SCC compared with wild-type mice. In the chemically induced SCC model, treatment of K14-Angptl2 Tg mice with the antioxidant N-acetyl cysteine (NAC) significantly reduced oxidative stress in skin tissue and the frequency of SCC development. Interestingly, K14-Angptl2 Tg mice in the model also showed significantly decreased expression of mRNA encoding the DNA mismatch repair enzyme Msh2 compared with wild-type mice and increased methylation of the Msh2 promoter in skin tissues. Msh2 expression in skin tissues of Tg mice was significantly increased by NAC treatment, as was Msh2 promoter demethylation. Overall, this study strongly suggests that the inflammatory mediator Angptl2 accelerates chemically induced carcinogenesis through increased oxidative stress and decreased Msh2 expression in skin tissue.

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Mitochondrial Dysfunction and Increased Reactive Oxygen Species Impair Insulin Secretion in Sphingomyelin Synthase 1-null Mice

Cited by 136 publications

References 49 publications

Serum sphingolipids: relationships to insulin sensitivity and changes with exercise in humans

Serum sphingolipids: relationships to insulin sensitivity and changes with exercise in humans

Dynamic Modification of Sphingomyelin in Lipid Microdomains Controls Development of Obesity, Fatty Liver, and Type 2 Diabetes

Angiopoietin-like Protein 2 Accelerates Carcinogenesis by Activating Chronic Inflammation and Oxidative Stress

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